Carbamates and carbanilates of 11-hydroxy - 10,5(epoxymethano)dibenzocyclohepten-13-one



United States PatentO 3,462,457 CARBAMATES AND CARBANILATES F 11-HY- DROXY 10,5(EPOXYMETHANO)DIBENZOCY- CLOHEPTEN-lS-ONE Martin A. Davis, Montreal, Quebec, and Thomas A. Dob son, St. Laurent, Quebec, Canada, assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Dec. 28, 1966, Ser. No. 606,519

Int. Cl. C07d 9/00, 29/12, 27/02 U.S. Cl. 260343.2 4 Claims ABSTRACT OF THE DISCLOSURE There are disclosed herein the compounds ll-carbamoyloxy-, 11 N methyl-carbamoyloxy, ll-N,N-dimethyl-carbamoyloxy-, 1l-N-ethyl-carbamoyloxy-, 11-N- propyl-carbamoyloxy-, ll-N-butyl-carbamoloxy-, 11-N- phenyl-carbamoyloxy-, l1-N-benzyl-carbamoyloxy-, 11- N-phenethyl-carbamoyloxy-, 1 1- (N-p-chlorobenzyl -carbamoyloxy-, 1 1-N-( l-naphthyl -carb amoyloxy-, 1 l-pyrrolidino-carbonyloxy-, l1-piperidino-carbonyloxy-, l1- morpholino-carbonyloxy-, and 11 N ethylpiperazinocarbonyloxy 10,5(epoxymethano)l0,1l dihydro-H- dibenzo[a,d]cyclohepten-l3-one. The compounds are useful as trichomonicidal agents and are prepared by reacting 11 hydroxy-10,5(epoxymethano)-10,1l-dihydro- 5H-dibenzo[a,d]cyclohepten-l3-one with either an appropriate hydrocarbon isocyanate or an aryl chloroformate and, in the latter case, reacting the product obtained with an appropriate amine. There is also disclosed the intermediate compound 11 phenoxycarbonyloiql 10,5 (epoxymethano) 10,11 dihydro-SH-dibenzo[a,d]cyclohepten-l3-one.

This invention relates to novel chemical compounds.

having useful biological properties. More particularly, this invention relates to novel carbamates and carbanilates of 11 hydroxy-10,5(epoxymethano)-l(),ll-dihydro-SH- dibenzocyclohepten-13-one of the following Formula I wherein R and R' represent hydrogen, a lower alkyl, group containing from 1-4 carbon atoms, aralkyl and halogen-substituted aralkyl groups containing from 7-8 carbon atoms, or aryl groups containing from 610 carbon atoms. In addition, the group NRR' may represent part of a heterocyclic ring, optionally containing an additional hetero atom, and containing from 4-6 carbon atoms and from 1-2 hetero atoms, such as, for example, pyrrolidine, piperidine, morpholine or N'-ethylpiperazine. Exemplary of the lower alkyl, aralkyl, substituted aralkyl and aryl substituents are the methyl,

ethyl, propyl, butyl, benzyl, phenethyl, p-chlorobenzyl, phenyl, and naphthyl groups. I

The compounds of Formula I may be prepared in the following manner: Those compounds in which R represents hydrogen and R is as defined above may be secured by the action of an alkyl-, aralkyl-, or arylisocyanate of the formula RNCO on ll-hydroxy-10,5 (epoxymethano)-10,l l-dihydro SH-dibenzo [a,d]cyclohepten-l3-one of Formula II. The reaction is conveniently carried out in: an inert solvent such as, for example, anhydrous dioxane or benzene'optionally containing a small quantity of a tertiary organic base such as, for example, pyridine. The reaction mixture is left at room temperature for a period of time sufficient to effect completion of the reaction such as, for example, sixteen hours. The product is then separated and purified in the conventional manner.

Alternatively, for those compounds in which R and R have all the significances defined in the first instance, the following method may be employed: The ll-hydroxy compound of Formula II is treated with an aryl chloroformate, preferably phenyl chloroformate of the formula C H OCOCl. The reaction is conveniently carried out in an acid-binding solvent such as, for example, pyridine, and is performed at room temperature for a period of time sufiicient to effect the condensation, such as, for example, 2 to 10 hours. The product is isolated and purified in a conventional manner to afford ll-phenoxycarbonyloxy 10,5(epoxymethano) 10,11 dihydro 5H- dibenzo[a,d]cyclohepten-13-one of Formula III. This last-mentioned intermediate is then interacted with ammonia or an organic amine of the formula HNRR', wherein R and R and NRR are as defined above. The reaction is carried out at temperatures ranging from -30 to +30 C. and the desired product of Formula I is isolated and purified in a conventional manner.

The requisite starting material for the'compounds of this invention, i.e., the hydroxy compound of Formula II, may be prepared as described in our co-pending US). application S.N. 539,640, filed Apr. 4, 1966, now Patent 3,361,767 issued Jan. 2, 1968. Briefly, this process entails the treatment of 5H-dibenzo[a,d]cycloheptene-S- carboxamide, prepared as described by M. A. Davis et al. in J. Med. Chem. 7, 88 (1964), with one molar proportion of bromine. The resulting product is then warmed with water or an aqueous alkanol to furnish ll-bromo- 10,5(epoxymethano)10,11 dihydro 5H dibenzo [a,d] cyclohepten-l3-one, which is then interacted with liquid ammonia to furnish 10,1l-epoxy-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene-S-carboxamide. This compound, in turn, is treated with a mineral acid, preferably aqueous sulfuric acid, to furnish a mixture of the lower and higher-melting geometrical isomers of the desired 11- hydroxy-10,5(epoxymethano) 10,11-dihydro SH-dibenzo [a,d]cyclohepten-l3-one of Formula II.

The novel compounds of Formula I have useful biological properties and are of value as medicaments. They have activity against the parasitic organism Trichom onas foetus and are trichomonacidal agents. For this purpose, they may be formulated with suitable excipients as vaginal suppositories or vaginal inserts, each containing from 50- 500 mg. of the active ingredient and may be administered once to four times daily for periods of time of from two to four weeks.

II III II on on 00001 l 6 95 NCO Example l.11 phenoxycarbonyloxy 10,5(epoxymethano) 10,1l-dihydro-SH-dibenzo[a,d1cyclohepten- 13-one (III) A solution of l1-hydroxy-10,5(epoxymethano)10,11- dihydro-5H-dibenzo[a,d]cyclohepten-l3-one (1.0 g., 0.004 mole) in dry pyridine ml.) is treated with cooling and stirring with phenyl chloroformate (0.76 g., 0.005 mole). The solution is then stirred at room temperature for three hours and diluted with water ml.). The precipitated oil solidifies and is filtered off to furnish 1.6 g. of the title product. Recrystallization from ethanol furnishes a purified sample, M.P. 165166 C. Elemental analysis confirms the empirical formula C H O of the title compound.

Example 2.-l1 carbamoyloxy-10,5(epoxymethano) 10, 1l-dihydro-SH-dibenzo[a,dJcyclohepten 13 one (I, R=R=H) A solution of the phenyl carbonate ester prepared as described in Example 1 (1.0 g.) in dry ether (75 ml.) is treated with liquid ammonia (75 ml.). The mixture is allowed to stand at ambient temperature for two hours, allowing the ammonia to evaporate. The precipitated product is removed by filtration and washed with a little ether to furnish 0.9 g. of the title product. Recrystallization from a mixture of dioxane and ether furnishes the title compound with M.P. 263-265 C. Elemental analysis confirms the empirical formula C H NO Proceeding as described above, but substituting ammonia by methylamine, dimethylamine, propylamine, benzylamine, pyrrolidine, piperidine, morpholine, or N- ethylpiperazine, the corresponding l1-N-methyl-, 1l-N,N- dimethyl-, 1l-N-propyl-, or ll-N-benzyl-carbamoyloxyand the corresponding 11-pyrrolidino-, 11-piperidino-, 11- morpholinoor 11-N-ethylpiperazino-carbonyloxy-10,5 (epoxymethano) 10,11 dihydro-SH-dibenzo[a,d]cyclohepten-13-ones are obtained.

Example 3.-11 (N-phenyDcarbamoyloxy 10,5 (epoxymethano)10,'11-dihydro SH-dibenzo[a,d]cyclohepten- 13-one (I, R=H, R'==C H A solution of l1-hydroxy-10,5(epoxymethano)10,11- dihydro 5H dibenzo[a,d]cyclohepten-13-one (1.0 g., 0.004 mole) in dry benzene (10 ml.) containing dry dioxane (2.0 ml.), is treated with phenyl isocyanate (0.48 g., 0.004 mole) and two drops of dry pyridine. The solution is left at room temperature overnight, treated with water (25 ml.) and the benzene layer is separated, washed with water, dried and concentrated in vacuo. The residual material is recrystallized from ethanol to furnish the title product with M.P. 240241 C. The empirical formula C23H17NO4 is confirmed by elemental analysis.

Proceeding as directed above, but substituting the phenyl isocyanate by methyl, ethyl, propyl, butyl, benzyl, phenethyl, p-chlorobenzyl, or l-naphthylisocyanate, the corresponding 1l-N-methyl-, N-ethyl-, N-propyl-, N- butyl-, N-benzyl, N-phenethyl-, N-(p-chlorobenzyl)- or N l-naphthyl)-carbamoyloxy 10,5(epoxymethano) l0, 1l-dihydro-SH-dibenzo[a,d]cyclohepten-l3-ones are obtained.

We claim:

1. A compound selected from the group consisting of 11 carbamoyloxy 10,5(epoxymethano)10,11-dihydro- SH dibenzo[a,d]cyclohepten 13-one,11 N methylcarbamoyloxy 10,5 (epoxymethano)l0,11 dihydro-5H- dibenzo[a,d]cyclohepten l3 one,1l N,N-dimethylcarbamoyloxy 10,5 (epoxymethano) 10,11 dihydro-5H- dibenzo[a,d]cyclohepten 13 one,11-N-ethyl-carbamoyloxy 10,5 (epoxymethano) 10,11 dihydro SH-dibenzO [a,d]cyclohepten l3 one,ll N propylcarbamoylox-y- 10,5(epoxymethano) 10,11 dihydro 5H dibenzo[a,d] cyclohepten l3 0ne,l1 N butylcarbamoyloxy-IO,5 (epoxymethano)10,11-dihydro 5H dibenzo[a,d]cyclohepten 13 one,ll-N-phenylcarbamoyloxy-10,5(epoxymethano)10,1l dihydro SH-dibenzo[a,d]cyclohepten- 13 one,1l-N-benzyl-carbamoyloxy-l0,5(epoxymethano) 10,11 dihydro 5H dibenzo[a,d]cyclohepten 13-one, 11 N phenethyl-carbamoyloxy 10,5(epoxymethano) 10,11 dihydro 5H dibenzo[a,d]cyclohepten l3-one, ll (N-p-chlorobenzyl) carbamoyloxy 10,5 (epoxymethano)l0,1l dihydro 5H-dibenzo[a,d]cyclohepten- 13 one,11 N (l-naphthyl)-carbamoyloxy-l0,5 (epoxymethano) 10,11 dihydro 5H dibenzo[a,d] cyclohepten- 13 one, and 11 pyrrolidino-carbonyloxy 10,5(epoxymethano) 10,11 dihydro 5H dibenzo[a,d]cyclohepten- 13 one,1l piperidino-carbonyloxy-l0,5(epoxymethano) 10,11 dihydro 5H dibenzo[a,dJcyclohepten-l3-one, 11 morpholino carbonyloxy 10,5(epoxymethano) 10, 11 dihydro 5H-dibenzo[a,d]cyclohepten-l3-one, and 11 N-ethylpiperazino-carbonyloxy-10,5 (epoxymethano) 10,11 dihydro 5H dibenzo[a,d]cyclohepten-l3-one.

2. 11 carbamoyloxy 10,5(epoxymethano) 10,11 dihydro-SH-dibenzo[a,dJcyclohepten-13-one.

3. 1l-(N-phenyl)carbamoyloxy 10,5 (epoxymethano) 10,1I-dihydro-SH-dibenzo[a,d]cyclohepten-l3-one.

4. 11 phenoxycarbonyloxy l0,5(epoxymethano)l0, 1 l-dihydro-SH-dibenzo [a,d] cyclohepten-l3-one.

References Cited UNITED STATES PATENTS 3,391,163 7/1968 Dobson et a1 260343.2

JAMES A. PATIEN, Primary Examiner US. Cl. X.R. 

